Intermediate indolines

ABSTRACT

This disclosure describes intermediates useful for the preparation of substituted 3-(2-(4-phenyl-1piperazinyl)ethyl)indolines which possess tranquilizing activity.

United States Patent [191 Allen, Jr, et al.

[ Aug. 19, 1975 [73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: Apr. 12, 1973 [2|] Appl. No.: 350,445

Related US. Application Data [62] Division of Ser. No. 147,700, May 27,1971, Pat. No.

521 US. Cl. 260/326." R; 260/268 BC; 260/325 R; 424/250 [51] Int. Cl.C07D 209/12 [58] Field of Search 260/326.l1 R

[56] References Cited OTHER PUBLICATIONS McLean et al., Caimdian Journalof Chemistry, 1969, 47:3647-54.

Primary E.\aminerDonald G. Daus Assistant Examiner-Raymond V. RushAttorney, Agent, or FirmEdward A. Conroy, Jr.

[57] ABSTRACT This disclosure describes intermediates useful for thepreparation of substituted 3-[2-(4-phenyl-1- piperaziny])ethyl]indolineswhich possess tranquilizing activity.

9 Claims, N0 Drawings 1 INTERMEDIATE INDOLINES CROSS REFERENCE TORELATED APPLICATION This application is a division of our co-pendingapplication Ser. No. 147,700, filed May 27, 1971, now U.S. Pat. No.3,751,416.

BRIEF SUMMARY OF THE INVENTION This invention relates to new organiccompounds and, more particularly, is concerned with novel substituted3-[ 2-( 4-phenyll -piperazinyl )ethyl }indolines and with novelintermediates and novel methods for the preparation of these compounds.The novel substituted 3-[2-(4-phenyl-1-piperazinyl)ethyl]indolines ofthe present invention may be represented by the following generalformula:

R1 CH CH -N N l R R5 R1 ca cH -z R2 N; R r

wherein Y is benzoyl or lower alkanoyl; Z is hydroxy, chloro, bromo,methanesulfonyloxy or ptoluenesulfonyloxy; and R R and R are ashereinabove defined. Suitable lower alkoxy groups contemplated bythe'present invention are those having up to four carbon atoms such as,for example, methoxy, ethoxy, isopropoxy, sec-butoxy, etc. Suitablelower alkanoyl groups contemplated by the present invention are thosehaving from 2 to 4 carbon atoms such as acetyl, propionyl, n-butyryl andisobutyryl. Typical compounds of the present invention represented bygenera formula (1), above, are, for example, 6-methoxy-3-[2- (4-phenyll-piperazinyl )ethyl }indoline, 6-rriethoxy-3- {2-[ 4-( o-tolyl l-piperazinyl]ethyl} indoline, S-amino- 6-methoxy-3-[2-(4-phenyllpiperazinyl)ethyl }indoline, 5-bromo-3- {2-[ 4-( p-tolyl l -piperazinyl]ethyl} indoline, 5-chloro-2-methyl-3-[ 2-( 4-phenyll piperazinyl)ethyl }indoline, 5,6-dimethxy-3- 2-[ 4-( mtrifluoromethylphenyl l-piperazinly]ethyl }indoline, 6,7-dihydro-7+'{2-[ 4-(m-trifluoromethylphenyl lpiperazinyllethyl} -H-1,3-dioxolo[4,5-f]indole,5,6- dimethoxy-3-{2-[4-(m-methoxyphenyl)-1-piperazinyl]ethyl}-2-methylindoline, 6,7-dihydro-7-{2- 2[4-(p-methoxyphenyl)-l-piperazinyl]ethyl}-5H-1,3- dioxolo[4,5-f]indole,5-bromo-3-{2-[4- pchlorophenyl)-l-piperazinyl1ethyl} indoline, 5,6-dimethoxy-3-{2-[4-(m-chlorophenyl)-3-methyl-1- piperazinyl ethyl}-indoline 6,7- dihy dro-7- {2- 4-( pchlorophenyl )-3-methyll-piperazinyl ethyl} -5 I-ll ,3- dioxolo[ 4,5f] indole, 5-amino-3- 2-(4-phenyll piperazinyl )ethyl indoline, 5-dimethylamino-3- 2-[ 4-(mtrifluoromethylphenyl 1 -piperazinyl ethyl} indoline, 5-chloro-3-{ 2-4-( o-methoxyphenyl l piperazinyl ethyl} indoline, 3- {2- 4-( o-tolyl lpiperazinyl ]ethyl} indoline, 3- {2- 4-( p-tolyl)-2-methyll-piperazinyl] ethyl} indoline, 3- 2- [4-( m-tolyl lpiperazinyl ethyl} indoline, 5,6-dimethoxy-3- {2-[4-( otolyl l-piperazinyl]-ethyl -2-methylindoline, 5,6- dimethoxy-3- {2- [4-(m-tolyl l -piperaz inyl ethyl }-2- methylindoline, 6,7-dihydro-7- 2- 4-(mmethoxyphenyl l-piperazinyl ethyl }-5 H- 1 ,3 dioxolo[ 4,5-f] indole,5-methoxy-2-methy1-3-[2-(4- phenyl- 1-piperazinyl]ethyl-6-nitroindoline,S-methoxy- 2-methyl-3- {2- [4-(o-tolyl)- l -piperazinyl]ethy1}-indoline, S-methoxy- 2-methyl-3 2- 4-( m-tolyl l piperazinyl ]-ethyl}-6-nitroindoline, and 5 -amino-3- {2- [4-( m-methoxyphenyl I-piperazinyl ]ethyl indoline.

DETAILED DESCRIPTION OF THE INVENTION The substituted 3-[2-( 4-phenyll-piperazinyl )ethyl indolines of the present invention are obtainable ascrystalline materials having characteristic melting points andabsorption spectra. They are appreciably solublein many organic solventssuch as lower alkanols, acetone, ethyl acetate, and the like but aregenerally insoluble water. These compounds are organic bases and thusare capable of forming acid-addition and quaternary ammonium salts witha variety of organic and inorganic salt-forming reagents. Thus,acidaddition salts, formed by admixture of the organic free base with upto three equivalents of an acid, suitably in a-neutral solvent, areformed with such acids as sulfuric, phosphoric, hydrochloric,hydrobromic, sulfamic, citric, 'ma'leic, fumaric, tartaric, acetic,benzoic,gluconic, ascorbic, and related acids. In like manner,quaternary ammonium salts may be formed by reaction of the free baseswith a variety of organic esters of sulfuric, hydrohalic and aromaticsulfonic acids The organic reagents employed for quaternary ammoniumsalt formation are preferably lower alkyl halides. However, otherorganic reagents are suitable for quaternary ammonium salt formation andmay be selected from among a diverse class of compounds including benzylchloride, phenethyl chloride, naphthylmethyl bromide, dimethyl sulfate,methyl benzenesulfonate, ethyl toluenesulfonate, allyl chloride,methallyl bromide and crotyl bromide. The acid-addition and quaternaryammonium salts of the substituted 3-[2-(4-phenyl-lpiperazinyl)ethyl}indolines are, in general, crystallinesolids relatively soluble in water, methanol and ethanol but relativelyinsoluble in non-polar organic solvents such as diethyl ether, benzene,toluene, and the like. For purposes of this invention, the free basesare equivalent to their non-toxic acid-addition and quaternary ammoniumsalts.

Continued R6 CH CH -OH Ra (m m -R R2 R3 R2 I]: R3

Y (III) Y wherein R R R R and Y are as hereinabove defined; R ishydrogen, chloro, bromo, lower alkoxy, nitro, acetamido ormethylenedioxy when taken together with R and R is chloro, bromo,methanesulfonyloxy or p-toluenesulfonyloxy. In accordance with thisreaction scheme, treatment of a I-acyI-S-indoline ethanol (III) withphosphorus trichloride or phosphorus tribromide is productive of al-acyl-3-ind0line ethyl chloride or bromide (IV, R =Cl or Br),respectively. Alternatively, treatment of the l-acyl-3-indoline ethanol(III) with methanesulfonyl chloride or p-toluenesulfonyl chloride in asolvent such as pyridine or collidine gives the sulfonyl ester (IV, R=CH SO or -cH C,,-H,so Reaction of the intermediates (IV) with a4-phenylpiperazine of the formula:

HZN CH2CH2-N N /L R4 R2 N R3 l I Y cn cn -rf N@ I R5 Other compounds ofthe present invention may be prepared as indicated in the followingreaction sequence:

N R (VIII) ("0ntinued (CH3 )ZN cH cH -N N i R R2 III)\R3 i' 4 v W HaCH2CH2 N@ l q R 4 R2 a I I I (CH3 )2N :CH2CH2N N Q R 2 N s 4 i ifwherein R R R R5 and Y are as hereinabove dederivatives (IX) and (X)then gives the 5- fined. Thus, in accordance with this reaction scheme,reduction of a l-acyl-5-nitroindoline ethylamine (VIII) affords thel-acyl-S-aminoindoline ethylamine (IX). This reduction may be performedusing a metal in mineral acid or catalytically. The latter process isparticularly advantageous. Methylation of (IX) with formaldehyde andformic acid, according to the Eschweiler- Clarke. procedure, gives thel-acyl-S-dimethylamino derivatives (X). Mineral acid hydrolysis of thel-acyl e 4 aminoindoline ethylamine (XI) and the 5- dimethylaminoderivatives (XII), respectively.

The novel l-acyl-3-indoline ethanols (III) which may serve as startingmaterials for the substituted 3-[2-(4-phenyl-1-piperazinyl)ethyl]indolines (VI) may be prepared by severalprocedures. In those instances when R is hydrogen in (III), theappropriate l-acyl-3- indoline ethanol may be prepared as set forth inthe following reaction scheme:

cn co a (XVIII) 1i CH CH OH Continued e CH CH O-Y 6 l R2 N R2 (XIX)wherein R R and Y are as hereinabove defined and R is lower alkyl offrom 1 to 4 carbon atoms or phenyl lower alkyl such as benzyl,oz-phenethyl and B-phenethyl. In accordance with this reaction scheme,condensation of an oxindole (XIII) with an oxalate ester (such asdimethyl oxalate, diisopropyl oxalate, dibenzyl oxalate, etc.) affordsthe corresponding isatylidene ester (XIV). The last substance may beconverted into the l-acyl-3-indoline ethanols (XX) by several routes.Clemmensen reduction of the isatylidene ester (XIV) gives gheoxindoleacetic ester (XV). Diborane reduction of (XV) then gives theindoline ethanol (XVII).

CH CH OH N I Y hydride (Y O) under S ehott'en-Bauman conditions affordsthe l-acyl-3-indoline ethanol (XX) directly. Alternatively, treatment ofthe indoline ethanol (XVII) with an acyl halide or an acyl anhydride inpyridine produces the O, N-diacyl derivative (XIX). The O-acyl group maybe removed selectively to give the l-acyl-3- indoline ethanol (XX).Sodium methoxide in methanol is particularly useful for thisde-O-acylation. Solutions of ammonia or triethylamine in methanol mayalso be used for this selective deacylation.

Other l-acylindoline ethanols may be prepared from the known --acetyl3-indolineacetic'acids (XXI) as set Alternatively, the isatylidene ester(XIV) may be con- 25 forth in the following reaction scheme: CH2C2H V-ca co ii I COCHa C OCH (XXI R R2 l COCH? coca (XXIV) verted directlyinto the indoline ethanol (XVII) by reduction with excess diborane. Whenthe esterifying group (R,,) is benzyl, catalytic hydrogenation of theisatylidene ester (XIV) using a palladium-on-carbon catalyst affords theoxindoleacetic acid (XVI). This last substance may be converted into theindoline ethanols (XVII). Thus, treatment of (XVI) with a lower alkylchloroformate produces a mixed carbonic anhydride. Reduction of thiscarbonic anhydride with sodium borohydride gives the oxindolylethanol(XVIII). Treatment of (XVIII) with diborane then affords the indolineethanol (XVII). The conversion of (XVII) into the usefull-acyl-3-indoline ethanols (XX) may be accomplished by either of twoprocedures. Thus, treatment of (XVII) with an acyl halide (YCl or YBr)or an acyl anwherein R is -.chloro, bromo or nitro and R is ashereinabove defined. Thus, fl1e l-acetyl-3-indolineacetic acids (XXI)react with electrophilic agents to give the 5-substi tuted derivatives(XXII). Examples of such electrophilic agents are chlorine, bromine andnitric acid/ These reagents react with (XXI) to give the 5- choro,S-bromo and 5-nitro derivatives (XXII), respectively. The reactions maybe carried out in acetic acid at room temperature. Thel-acetyl-3-indolineacetic acids (XXI and XXII) may be reduced to givethe lacetylindoline ethanols (XXIII and XXIV), respectively. Diborane isparticularly effective for this transformation. Alternatively, the acidsmay be converted into mixed carbonic anhydrides by reaction with a loweralkyl chloroformate. Treatment of these mixed when the 3-indoleaceticester (XXV) has a methyl group at the 2-position, since these conditionslead to a great degree of stereoselectivity. Other reductive proceduresthat have been used with a degree of success for the conversion of (XXV)to (XXVI) are catalytic hydrogenation in the presence of a noble metalcatalyst under neutral or acidic conditions. Suitable catalysts areplatinum, palladium, ruthenium, and the like. Appropriate solvents arethose selected from the lower alkanols and mixtures of the loweralkanols with hydrochloric or fluoroboric acid. Treatment of the 3-indolineacetic ester (XXVI) with a metal hydride such as lithiumaluminum hydride is productive of the indoline ethanol (XXVII). Theresulting indoline ethanol (XXVII) may be acylated with an acyl chloride(YCl) or anhydride (Y O) to give the l-acyl derivative 10 CH2CO2R8 R10CH2CO2-R8 R3 N R3 |v H H (XXVI) 10 ZCHgOH R H Y (XXVII 7 (mm) 0 CHQCHZOHOQN R3 (XXIX) wherein R is lower alkoxy and R R and Y are as 50(XXVIII). Treatment of the l-acyl derivative (XXVIll) hereinabovedefined. Thus, reduction of a 3- indoleacetic ester (XXV) gives thecorresponding 3- indolineacetic ester (XXVI). This reduction may beperformed in several-ways. The utilizationof metallic with nitric acidin acetic acid gives the l-acyl-6-nitro-3- indoline ethanol (XXIX).

' Other important l-acyl-3-indoline ethanols may be obtained inaccordance with the following reaction tin an dhydrochloric acid isparticularly advantageous 55 scheme:

(XXX) CH2CO2-R8 R10v CH2CO2-R8 (XXXI) -Continued i CH CH O-Y o V R11 NR3 R11 l Y (XXXIII) R CHECHEOH Y (XXXIV) wherein R is lower alkoxy, Rand R taken together is methylenedioxy and R R R and Y are ashereinabove defined. The reduction of the 3-indoleacetic esters (XXX) tothe corresponding 3-indolineacetic esters (XXXl) is carried out in amanner analogous to the reduction of (XXV) to (XXVI). Reduction of the3- indolineacetic esters (XXXl) with a metal hydride reagent, such aslithium aluminum hydride, is productive of the 3-indoline ethanols(XXXlI). This last substance may be converted directly into the usefull-acyl-3- indoline ethanol (XXXIV) by acylation under Schotten-Baumanconditions with the appropriate acyl halide (YCl or YBr) or acylanhydride (Y O). Alternatively, treatment of XXXll) with an acyl halideor acyl anhydride in a solvent such as pyridine, lutidine, collidine,and the like gives the O,N-diacyl derivative (XXXlll). Treatment of(XXXIll) with sodium methoxide in methanol then gives the importantl-acyl-3- indoline ethanol (XXXlV).

The compounds of general formula (I) of the present invention arephysiologically active on the central nervous system and show highactivity as tranquilizers at non-toxic doses. A useful test fortranquilizer activity consists of measuring the reduction of spontaneousmotor activity in animals by means of an actophotometer (a photoelectricdevice for quantitatively measuring locomotor activity). Graded doses ofthe active compounds prepared by the processes of this invention areadministered to groups of mice, and the effective dosage range for asignificant reduction of motor activity (a measure of tranquilization)compared to control groups is established. The use of reduced motoractivity as a measure of tranquilizing activity has been described by W.D. Gray, A. C. Osterberg and C. E. Rauh, Archives lnternationales et deTherapie, Vol. 134, p. 198 1961) and W. J. Kinnard and C. J. Carr,Journal of Pharmacology and Experimental Therapeutics, Vol. l2l, p. 354(1957).

The effective dose that caused a 50 percent reduction in motor activity(MDD expressed in milligrams per kilogram of body weight, of sometypical com pounds of the present invention is set forth in Table lbelow.

CH CH 0H (XXXII TABLE I m Compound (mg/ 3-{ 2-(4phenyll -pipcmzinyl)cthyl ]indolinc l3 dimaleate 3- 2-[4-( o-methoxyphenyl l pipcrazinyl]cthyl}- 7 in oline trihydrochloridc 5.odimethoxy-2-mcthyl-3-[ 2-(4-phenyll 0.2 pipcrazinyl )eth l]indoline 6.7-dihydro-7- 2-[ 4-(o-mcthoxyphcnyl l l, l pipcrazinyl ]cthyl}-5H- l .3-dioxolo[4,5-f]-indole difumaratc 5-methoxy-2-methyl3-[ 2-( 4phenyll -pipcral2 zinyl)ethyl ]indolinc SmethoxyQ-mcthyl-B- {2-[ 4-( o-mcthoxyphenyl 25l-pipcrazinyl ]ethyl}indolinc 5-mcthoxy-3- {2-[ 4( o-mcthoxyphcnyl l-pipcral9 zin l]ethyl}'2-methyl-o-nitroindolinc 3- 2-[ 4-(o-methoxyphcnyl l -pipcruzinyl ]cthyl)- 6 S-nitroindolincdihydrochloride 5,6-dimcthoxy-3- {2[ 4-(o-mcthoxyphcnyl l-pipcra- 9zinyl lcthyl} indoline trihydrochloridc The invention will be describedin greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of 3-(2-hydroxyethyl)-2-indolinone To a solutionof 2.35 g. of oxindole-3-acetic acid J Am. Chem. Soc. 75, 5305 (1953)]in 18 ml. of tetrahydrofuran at 5C. in an argon atmosphere is added 1.71ml. of triethylamine and then 1.53 ml. of ethyl chlorocarbonate. Themixture is stirred at 5C. for 30 minutes and then filtered. The filtrateis added dropwise to a cold solution of 1.16 g. of sodium borohydride inl8 ml. of water, and the solution is then stirred at ambient temperaturefor 2 hours. The reaction mixture is rendered strongly acid withhydrochloric acid and extracted ,with ethyl acetate. The organicextracts are washed successively with saturated sodium chloridesolutionQsodium hydroxide solution and with saturated sodium chloridesolution. The organic extract is dried with magnesium sulfate andevaporated under reduced Preparation of 3-indolineethanol A solution of531 mg. of 3-(2-hydroxyethyl)-2-- indolinone in 35 ml. oftetrahydrofuran is purged with argon and 6.5 ml. of 1M borane intetrahydrofuran is added. The solution is heated under reflux for 18hours, then the solvent is removed under reduced pressure. The residualglass is dissolved in 35 ml. of methanol and heated under reflux for 4hours. The methanol is removed under reduced pressure and the residualgum is dissolved in 25 ml. of ethyl acetate. The organic solution isextracted with two 15 ml. portions of 1N hydrochloric acid. The acidextract is rendered alkaline with sodium hydroxide and extracted withethyl acetate. The organic extract is washed with saturated sodiumchloride solution, dried with magnesium sulfate and evaporated underreduced pressure affording 3- indolineethanol as an oil.

EXAMPLE 3 Preparation of 1-acetyl-3-indolineethanol To a suspension of l1.3 g. of l-acetyl-3-indoline acetic acid [.1. Org. Chem. 28, 27941963)] in 90 ml. of tetrahydrofuran at C. is added 9.0 ml.triethylamine. The resultant solution is stirred at -C. and 6.3 ml. ofethyl chlorocarbonate is added dropwise. The reaction mixture is alb wedto rise to 28C. over a period of 30 minutes and then filtered free oftriethylamine hydrochloride. The clear filtrate is added dropwise to asolution of 5.95 g. of sodium borohydride in 90 ml. of water stirred inan ice-bath and stirring is continued for two hours at room temperature.The reaction mixture is again stirred in an ice-bath and acidified with1N hydrochloric acid. The acid solution is extracted with ethyl acetateand the organic extract is washed with saturated sodium bicarbonatesolution, dried with magnesium sulfate and concentrated under reducedpressure leaving a clear gum weighing 5.2 g. The crude product isdissolved in methylene chloride and passed thru a column of syntheticmagnesium silicate collecting that fraction eluted by2:8-acetone:methylene chloride. The resulting gum is crystallized fromethyl ether affording 2.5 g. of l-acetyl-3-indolineetahnol, m.p. 4952C.

EXAMPLE 4 Preparation of 1-acetyl-3-indolineethanol To a suspension of4.38 g. of l-acetyl-3-indoline acetic acid in 45 ml. of tetrahydrofuranat 19C. is added dropwise 25 ml. of 1M borane in tetrahydrofuran. Thesolution is stirred for one hour, then diluted with 20 ml. of water and30 ml. of saturated sodium chloride solution. The mixture is extractedwith ether and the organic extract is washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution, thenextracted with 6N hydrochloric acid solution. The acid extract isrendered alkaline with ION sodium hydroxide solution and extracted withether. The ether extract is washed with saturated sodium chloridesolution, dried with magnesium sulfate and evaporated under reducedpressure affording 3.02 g. of l-acetyl-3-indolineethanol as a gum ofsufficient purity for subsequent reactions.

EXAMPLE 5 Preparation of ethyl 5,6-dimethoxy-2-oxo-A lindolineglycolateTo a solution of 4.82 g. of 5,6-dimethoxyoxindole [J. Am. Chem. Soc. 77,3844 1953)] in 50 ml. ofdimethylformamide stirred in an ice-bath in anargon atmosphere is added 1.25 g. of a sodium hydride in oil dispersion(60.2% concentration). The mixture is stirred for 30 minutes and then asolution of 5.35 g. of diethyl oxalate in 25 ml. of dimethylformamide isadded dropwise. The solution is stirred at ambient temperature for 18hours, then diluted with 150 ml. of water. The aqueous solution isstirred in an ice-bath and acidified with hydrochloric acid. Theresultant red solid is collected and recrystallized from acetoneaffording ethyl 5,6- dimethoxy-2-oxo-A a -indolineglycolate, m.p.183185C. dec.

EXAMPLE 6 Preparation of ethyl 5 ,6-dimethoxy-2-oxo-3-indolineacetate Toa suspension of 0.73 g. of 5,6-dimethoxy-2-oxoindolineglycolic acidethyl ester in 50 ml. of acetic acid is added freshly prepared zincamalgam (from 11 g. zinc and 1.1 g. mercuric chloride). The mixture isstirred under reflux for 16 hours. The mixture is cooled and filteredand the filtrate is reduced in volume to 10 ml. under reduced pressure.The residue is diluted with 50 ml. of water and extracted with ether.The ether extract is washed with saturated sodium carbonate solution andsaturated sodium chloride solution, then dried with magnesium sulfateand evaporated to dryness under reduced pressure. The resultant solidmass crystalalizes from acetone-petroleum ether (3060C.) affording ethyl5,6-dimethoxy-2-oxo-3-indolineacetate, m.p. l23l24C.

EXAMPLE 7 Preparation of 5,6-dimethoxy-3-indolineethanol To a solutionof 1.95 g. of 5,6-dimethoxy-2-oxo-3- indolineacetic acid ethyl ester in100 ml. of tetrahydrofuran stirred in an ice-bath in an argon atmosphereis added 40 ml. of 1M borane in tetrahydrofuran. The mixture is stirredfor 15 hours at ambient temperature and then heated under reflux for 18hours. The solvent is removed under reduced pressure and the residue isheated at 100C. with 100 ml. 1N hydrochloric acid. The acid solution iscooled and washed with ethyl acetate, then cooled in an ice-bath andmade alkaline with aqueous sodium hydroxide solution. The alkalinesolution is extracted with ethyl acetate. The organic extract is washedwith saturated sodium chloride, dried with magnesium sulfate andevaporated under reduced pressure affording 1.23 g. of 5,6-dimethoxy-3-indolineethanol as a gum.

EXAMPLE 8 Preparation of 6,7-dimethoxy-3-indolineethanol To a partialsolution of 2.93 g. of ethyl 5,6- dimethoxy-Z-oxo-A -indolineglycolatein 150 ml. of tetrahydrofuran stirred at 5C. in an atmosphere of argonis added ml. of a 1M solution of borane in tetrahydrofuran. The solutionis stirred at 5C. for one hour, stirred at ambient temperature for threehours and finally heated at reflux temperature for eighteen hours. Thesolvent is removed under reduced pressure and the residue is heated withml. of 1N sodium hydroxide on the steam bath for one hour. The cooledalkaline solution is extracted with ethyl acetate. The

ethyl acetate solution is extracted with 1N hydrochloric acid. Thehydrochloric acid extract is rendered alkaline with 5N sodium hydroxide,extracted with ethyl acetate and the extract evaporated under reducedpressure affording 0.82 g. of 6,7-dimethoxy-3-indolineethanol.

EXAMPLE 9 Preparation of 1 -acety1-5 ,6-dimethoxy-3-indolineethanol Asolution of 1.23 g. of 5,6-dimethoxyindoline-3- ethanol in 60 ml. of0.5N hydrochloric acid is rendered alkaline with ION sodium hydroxide.The mixture is stirred in an ice-bath and 12 ml. of acetic anhydride isadded dropwise. The mixture is stirred at ambient temperature for 15minutes maintaining alkalinity by addition of sodium hydroxide solution.An additional 12 ml. of acetic anhydride is added and the mixture isstirred for one hour. The solution is extracted with ethyl acetate andthe extracts are washed with saturated sodium chloride solution, driedwith magnesium sulfate solution and evaporated under reduced pressure.The residual gum is crystallized from acetone-petroleum ether (3060C.)affording l-acetyl-5,6-dimethoxy-3- indolineethanol, m.p. 148l50C.

EXAMPLE Preparation of 4,5-methylenedioxy-2-nitrophenylacetic acid Asuspension of 25 g. of 4,5-methylenedioxyphenyl acetic acid [.I. Org.Chem. 17, 568 (1952)] in 110 ml. of acetic acid is stirred at C. while40.5 ml. of concentrated nitric acid is added in portions maintainingthe temperature at 40C. The mixture is stirred for an additional 40min., then added to 800 m1. of ice water. The4,5-methylenedioxy-Z-nitrophenylacetic acid is collected as 24.5 g. ofyellow crystals, m.p. 185l88C.

EXAMPLE 1 1 Preparation of methyl 4,5-methylenedioxy-2-nitrophenylacetate A solution of 25 g. of4,5-methylenedioxy-2- nitrophenylacetic acid and 1 ml. concentratedsulfuric acid in 500 ml. methanol is heated at reflux temperature for 18hours. The solution is cooled and 5 g. of anhydrous sodium acetate isadded. The resultant precipitate is collected and washed with wateraffording 17.8 g. of methyl 4,5-methylenedioxy-2-nitrophenylacetate,m.p. l06-108C. Dilution of the filtrate with water affords an additional5.8 g. of product, m.p. 106108C.

EXAMPLE 12 Preparation of methyl 2-amino-4,5-methylenedioxyphenylacetateA mixture of 1 1 g. of methyl 2-nitro-4,5- methylenedioxyphenylacetateand 1.1 g. of 10 per cent palladium-on-charcoal catalyst in 200 ml. ofethanol is shaken with hydrogen until the theoretical amount of hydrogenis absorbed. The reaction mixture is filtered free of catalyst andevaporated under reduced pressure affording methyl2-amino-4,S-methylenedioxyphenylacetate as a white solid.

EXAMPLE 13 Preparation of 5,7-dihydro-6H-1,3-dioxolo[4,5-f]indol-6-one Asolution of 1.0 g. of methyl 2-amino-4,5- methylenedioxyphenylacetate in5 ml. of acetic acid is purged with argon and heated under reflux for 1hour. The hot acetic acid solution is stirred and diluted with wateruntil crystals form. The mixture is cooled and 660 mg. of5,7-dihydro-6H-l,3-dioxolo[4,5-f]-indol- 6-one, m.p. 222-225C., iscollected by filtration.

EXAMPLE 14 Preparation of ethyl 5,6-dihydro-6-oxo71-1-l,3-dioxolo[4,5-f]-indole-A -glycolate A solution of 5.31 g. of5,7-dihydro-6H-l ,3-dioxolo- [4,5-f]indol-6-one in 50 ml. ofdimethylformamide is stirred in an ice-bath in an argon atmosphere with1.45 g. of sodium hydride-in-oil dispersion (60.2 per centconcentration) for 30 minutes. To the reaction mixture is added asolution of 6.07 ml. of diethyl oxalate in 25 ml. of dimethylformamide.The reaction solution is stirred at ambient temperature for 18 hours,then added to 150 ml. of water and acidified with concentratedhydrochloric acid. The resultant red precipitate is collected byfiltration and recrystallized from acetone affording ethyl5,6-dihydro-6-oxo-71-l-1,3- dioxolo[4,5-f]indole-N' -glycolate, m.p.246248C.

EXAMPLE 15 Preparation of ethyl 5 ,6-dihydro-6-oxo-7l-l- 1 ,3-dioxolo[4,5-f]-indole- 7-acetate A suspension of 1.39 g. of ethyl5,6-dihydro-6-oxo- 7H-1,3-dioxolo[4,5-f]indole-A -glycolate and 1.39 g.of 10 per cent palladium-on-charcoal catalyst in 50 ml. of acetic acidcontaining 0.25 ml. concentrated sulfuric acid is shaken with hydrogenuntil two mole equivalents of hydrogen are absorbed. The reactionmixture is filtered directly onto 1.0 g. of anhydrous sodium acetate andthe filtrate is evaporated under reduced pressure. The residue ispartitioned between water and ethyl acetate. The ethyl acetate solutionis evaporated in vacuo and the residue crystallized fromacetone-petroleum ether (3060C.) affording ethyl 5,6-dihydro-6-oxo-7l-ll ,3-dioxolo[ 4,5-f]indole- 7-acetate, m.p. 15 l-l52C.

EXAMPLE 16 Preparation of ethyl 5,6-dihydro-6-oxo-7H- l ,3-dioxolo[4,5-f]-indole- 7-acetate To a suspension of 1.39 g. of ethyl5,6-dihydro-6- oXo-7H-l,3-dioxolo[4,5-f]indole-A -glycolate in 50 ml. ofacetic acid is added zinc amalgam prepared from 1 l g. of zinc and 1.1g. mercuric chloride. The mixture is stirred and heated at reflux for 18hours, then cooled and filtered. The filtrate is evaporated underreduced pressure to a volume of 10 ml. and diluted with m1. of water.The solution is extracted with ethyl acetate and the extracts washedsuccessively with saline solution, sodium bicarbonate solution and withsaline solutiion. The ethyl acetate is evaporated under reduced pressureand the residue crystallized from acetonepetroleum ether (3060C.)affording ethyl 5,6-dihydro-6-oxo-7H-1,3-dioxolo[4,5-flindole-7-acetate, m.p. l51C.

EXAMPLE 17 Preparation of 6,7-dihydro-5H- 1,3-dioxolo[4,5-f]indole-7-ethanol To a solution of l .0 got ethyl5,6-dihydro-6-oxo-7l-ll,3-dioxolo[4,5-f]indole-7-acetate in 50 ml. oftetrahydrofuran stirred at 5C. in an atmosphere of argon is added 21.8ml. of a 1M solution of borane in tetrahydrofuran. The solution isstirred at C. for 15 minutes, at ambient temperature for 90 minutes andfinally heated at reflux for 18 hours. The solvent is removed underreduced pressure and the residue is heated on the steam bath with 50 ml.of 1N hydrochloric acid for one hour. The solution is washed with ethylacetate, rendered alkaline with ION sodium hydroxide and extracted withethyl acetate. The solvent is removed under reduced pressure leaving 0.6g. of 6,7-dihydro- H-l ,3-dioxolo[4,5-f]indole-7-ethanol as an amberoil.

EXAMPLE 18 Preparation of 5-acetyl-6,7-dihydro-5l-ll,3-dioxolo[4,5-f]indole'7 ethyl acetate A solution of 0.6 g. of6,7-dihydro-5H-l,3-dioxolo- [4,5-f]indole-7-ethanol in ml. of pyridineand 0.9 ml. of acetic anhydride is heated on the steam bath for twohours. The solution is cooled, diluted with water and extracted withethyl acetate. The extract is washed with 1N hydrochloric acid andsaline solution and evaporated under reduced pressure. The residue iscrystallized from acetone-petroleum ether (3060C.) affording5-acetyl-6,7-dihydro-5H- l ,3-diox0lo[ 4,5- f]indole-7-ethylacetate,m.p. 9394C.

EXAMPLE 19 Preparation of5-acetyl-6,7-dihydro-5H-1,3-dioxolo[4,5-f]indole-.7- ethanol A solutionof 200 mg. of 5-acetyl-6,7-dihydro-5H-l,3-dioxolo[4,5-f]indole-7-ethylacetate and 40 mg. of sodium methoxidein 10 ml. of methanol is heated at reflux for 2 hours, then evaporatedunder reduced pressure. The residue is partitioned between ethyl acetateand water. The ethyl acetate solution is separated and evaporated underreduced pressure. The residue is crystallized from acetone-petroleumether (3060C.) affording 5-acetyl-6,7 dihydro-5H- l ,3-dioxolo[4,5-flindole-7-ethanol, m.p. l40l4lC.

EXAMPLE 20 Preparation of l-acetyl-5-nitro-3-indoline acetic acid To astirred mixture of 34.21 g. (0.16 mol) of l-acetyl-3-indoline aceticacid [J. Org. Chem., 28, 2794 (1963)] and 450 ml. of glacial acetic acidis added dropwise at 15C. 233 ml. of 90% fuming nitric acid. Theresulting solution is stirred at room temperature for one hour and thenpoured onto 1,100 g. of cracked ice. The solid is collected byfiltration to give 32.25 g. of bright yellow crystals, m.p. 20821 1C.

EXAMPLE 21 Preparation of 1-acetyl-5-bromo-3-indolineacetic acid Asolution of 4.00 g. (25 mmol, 1.3 ml.) of bromine in 12.5 ml. of aceticacid is added dropwise to a stirred mixture of 5.10 g. (22.5 mmol) of1-acetyl-3- indolineacetic acid in 25 ml. of glacial acetic acid. The

resulting solution is stirred at ambient temperature for min. and isthen poured into 150 ml. of water. The precipitated solid isrecrystallized from isopropyl alcohol to give white crystals, m.p.l197C.

EXAMPLE 22 Preparation of l-acety1-5-chloro-3-indolineacetic acid Asolution of 1.55 g. (22 mmol) of chlorine in 15 m1. of glacial aceticacid is added to a stirred mixture of 4.40 g. (20 mmol) of 1acety1-3-indolineacetic acid in 20 ml. of acetic acid.The mixture isstirred at ambient temperature for one hour, during which the soliddissolved. The solution is diluted with water, and the precipitatedsolid is recrystallized from isopropyl alcohol to give white crystals,m.p. l90193C.

EXAMPLE 23 Preparation of l-acety15-nitro-3-indolineethanol To a stirredmixture of 29.43 g. (0.118 mol) of lacetyl-S-nitro-3-indolineacetic acidin 500 ml. of tetrahydrofuran is added dropwise over 45 minutes ml. of1M borane in tetrahydrofuran solution. The resulting solution is stirredat room temperature for 90 minutes, whereafter 25 ml. of water is addeddropwise. The solvents are removed under reduced pressure, and theresidue is distributed between ethyl acetate and sodium carbonatesolution. The organic layer is washed with additional sodium carbonatesolution, dried and concentrated under reduced pressure until a mass ofyellow crystals separate. The solid is recrystallized from ethylacetate-heptane to give yellow crystals, m.p. l39-l4lC.

EXAMPLE 24 Preparation of 1-acetyl5-bromo-3-indolineethanol In themanner described in Example 23 treatment of 6.07 g. (20.4 mmol) ofl-acetyl-5-bromo-3- indolineacetic acid in 50 ml. of tetrahydrofuranwith 20 ml. of 1M borane in tetrahydrofuran solution gives whitecrystals.

EXAMPLE 25 Preparation of 1-acetyl-5-chloro-3-indoleethanol In themanner described in Example 23 treatment of 3.29 g. (13 mmol) of1-acetyl-5-chlor0-3- indolineacetic acid in 50 ml. of tetrahydrofuranwith 13 ml. of 1M borane in tetrahydrofuran solution affords whitecrystals, m.p. 103l06C. Recrystallization several times fromacetone-hexane raises the m.p. to l l8l 19C.

EXAMPLE 26 Preparation of 1-acetyl-5-amino-3-indolineethanol A mixtureof 3.0 g. (0.012 mole) of l-acetyl-S-nitro- 3-indolineethanol and 300mg. of 83% platinum oxide in 200 ml. of ethanol is shaken under 40 psi.of hydrogen for 30 min. The catalyst is separated by filtration and thefiltrate is dried over magnesium sulfate and concentrated to yieldl-acetyl-5-amino-3- indolineethanol as a yellow oil.

EXAMPLE 27 Preparation of N-[ l-acetyl-3-( 2-acetoxyethyl)-5-indo1inyl]acetamide A solution of 3.1 g. (0.014 mole) of l-acetyl-S-amino-3-indolineethanol in 40 ml. of pyridine and ml. of aceticanhydride is warmed on a steam bath for 30 min. After dilution withwater the mixture is extracted with ethyl acetate. The extract is washedwith 1N hydrochloric acid, dried over magnesium sulfate, andconcentrated. The residue is crystallized from acetone to yieldN-[l-acetyl-3-(2-acetoxyethyl)-5-indolinyl]- acetamide, m.p. l63l64C.

EXAMPLE 28 Preparation of N-[ l-acetyl3-( Z-hydroxyethyl)-5-indolinyl]acetamide A mixture of 1.4 g. (0.0046 mole) ofN-[1-acetyl3- (Z-hydroxyethyl)-5-indolinyl]acetamide, acetate and 0.50g. (0.0093 mole) of sodium methoxide in 40 ml. of methanol is stirredunder reflux for 30 min. The methanol is removed by distillation and theresidual oil is dissolved in water and extracted with ethyl acetate. Theextract is dried over magnesium sulfate and concentrated. The residue isrecrystallized from acetoneether to yieldN-[1-acetyl-3-(2-hydroxyethyl)-5- indolinyl]acetamide, m.p. 181l82C.

EXAMPLE 29 Preparation of ethyl 5-methoxy-2-methyl-3-indolineacetate Amixture of 25 g. (0.11 mole) of 5-methoxy2- methyl-3-indoleacetic acid,260 ml. of hydrochloric acid, 260 ml. of ethanol and 104 g. of tin isheated under reflux three days and filtered. The filtrate isconcentrated and the residual oil is dissolved in ethanol previouslysaturated with hydrogen chloride. This mixture is stirred under refluxfor 16 hours and then concentrated. The concentrate is rendered alkalinewith saturated sodium bicarbonate solution. The mixture is filtered andthe filtrate is extracted with ether. The ether extract is washed withsaturated sodium bicarbonate and saturated sodium chloride solution,dried over magnesium sulfate, filtered, and concentrated to yield ethyl5-methoxy-2-methyl-3-indolineacetate' a lightly colored oil.

EXAMPLE 30 Preparation of 2-methyl5-methoxy-3-indolineethanol To astirred suspension of 7.5 g. (0.20 mol) of lithium aluminum hydride in1.5 1. tetrahydrofuran is added 27 g. (0.1 1 mol) of ethyl2-methyl-5-methoxy-3- indolineacetic acid. The mixture is stirred atreflux for 18 hours, cooled and an aqueous solution of sodium potassiumtartrate is added. The reaction mixture is filtered and the filter cakeis washed with ethyl acetate. The filtrate is concentrated to an oilwhich is dissolved in benzene, treated with activated carbon, dried overmagnesium sulfate, filtered through diatomaceous earth and evaporatedunder reduced pressure. The resulting oil is cooled in the refrigeratorto afford 2- methyl-5-methoxy-3-indolineethanol as gray white crystals,m.p. 798lC.

EXAMPLE 31 Preparation of l-acetyl-2-methyl-5-methoxy-3-indolineethanolTo a stirred suspension of g. (0.05 mole) of 2-methyl-S-methoxy-3-indolineethanol in 0.5 l. of ION sodium hydroxide isadded 9.9 g. (0.10 mole) acetic anhydride. After being allowed to stirovernight the reaction mixture is extracted with ethyl acetate. Theorganic layer is washed with 1N hydrochloric acid and saturated aqueoussodium chloride. The organic layer is dried over magnesium sulfate,filtered and the filtrate concentrated to a clear oil. The oil issuspended in l l. of 2N sodium hydroxide solution and allowed to stirovernight. The reaction mixture is filtered and the filter cake washedwith ether and petroleum ether to affordl-acetyl-2methyl-5methoxy-3-indolineethanol as offwhite crystals, m.p.71-73C.

EXAMPLE 32 Preparation of1-acetyl-2-methyl-5-methoxy-6-nitro-3-indolineethanol A solution of 1.00g. of 1-acetyl-2-methyl-5- methoxy-3-indolineethanol in 25 ml. ofglacial acetic acid is stirred in an ice bath and treated with 1 ml. offuming nitric acid. The solution is stirred at room temperature for onehour and poured onto cracked ice to give orange crystals of1-acetyl-2-methyl-5-methoxy-6- nitro-3-indolineethanol.

EXAMPLE 33 Preparation of ethyl 5,6-dimethoxy-2-methyl-3-indole acetateA mixture of 3.8 g. (0.019 mole) of 3,4-dimethoxyphenylhydrazinehydrochloride, 2.4 ml. (0.017 mole) of ethyl levulinate, and 40 ml. ofethanolic hydrogen chloride is stirred under reflux for 30 minutes. Theethanol is evaporated under reduced pressure and the residue is dilutedwith water and extracted with ether. The extract is washed with aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrated under reduced pressure. Crystallization from etherpetroleumether affords ethyl 5,6-dimethoxy-2-methyl- 3-indole acetate, m.p.7879C.

EXAMPLE 34 Preparation of ethyl 5,6-dimethoxy-2-methyl-3-indolineacetate A mixture of 3.0 g. (0.01 1 mole) of ethyl 5,6-dimethoxy-2-methyl-3-indole acetate, 7.0 g. (0.059 mole) of tin, 35 ml.of ethanol, and 35 ml. of concentrated hydrochloric acid is heated underreflux for one hour. An additional 7.0 g. (0.059 mole) of tin is addedand the mixture is heated under reflux for six hours. Excess tin isseparated by filtration and the filtrate is evaporated under reducedpressure. The residue is diluted with Water, rendered alkaline withaqueous sodium hydroxide solution, and extracted with ethyl acetate. Theextract is dried over magnesium sulfate and concentrated under reducedpressure to yield ethyl 5,6- dimethoxy-2-methyl-3indoline acetate as ayellow oil.

EXAMPLE 35 Preparation of 5 ,6-dimethoxy-2-m ethyl-3-indolineethanol Asuspension of 10 g. (0.26 mole) of lithium aluminum hydride in 300 ml.of tetrahydrofuran is stirred under an argon atmosphere while a solutionof 20 g. (0.072 mole) of ethyl 5,6-dimethoxy-2-methyl-3- indolineacetatein ml. of tetrahydrofuran is added. The mixture is stirred under refluxfor two hours and then treated with aqueous sodium potassium tartratesolution. The precipitate is separated by filtration and washed withethyl acetate. The filtrate is dried over magnesium sulfate andconcentrated under reduced pressure to yield 5,6-dimethoxy-2-methyl-3-indolineethanol as a yellow oil.

EXAMPLE 36 Preparation of l-benzoyl-S,6dimethoxy-2-methyl-3-indolineethyl benzoate EXAMPLE 37 Preparation ofl-benzoyl-5,6-dimethoxy-2-methyl3-indolineethanol To a suspension of3.0g. (0.0068 mole) of l-benzoyl- 5,6-dimethoxy-Z-methyl-3-indolineethy]benzoate in 20 ml. of methanol is added 1.5 g. (0.028 mole) of sodiummethoxide. The mixture is stirred under reflux for one hour and thenevaporated under reduced pressure. The residue is diluted with water andextracted with ethyl acetate. The extract is dried over magnesiumsulfate and concentrated in vacuo to yield 1-benzoyl-5,6-dimethoxy-2-methyl3-indolineethanol as a yellow oil.

EXAMPLE 38 Preparation of -methoxy-2-methyll -(p-nitrobenzoyl)-3-indolineethanol A solution of 415 mg. (2.0 mmol) of 5methoxy-2-methyl-3-indolineethanol in 5 ml. of methylene chloride is treated with200 mg. (5.0 mmol) of sodium hydroxide in 5 ml. of water. The mixture istreated with a solution of 375 mg. (2.0 mmol) of p-nitrobenzoyl chloridein 5 ml. of methylene chloride and stirred at room temperature for 16hours. The mixture is separated, and the organic layer is washed withwater and saline, dried and evaporated to give a yellow oil whichcrystallizes from ether-hexane to give yellow prisms, m.p. l35l38CEXAMPLE 39 Preparation of S-methoxy-Z-methyll -(p-chlorobenzoyl)-3-indolineethanol A solution of 415 mg. (2.0 mmol) of 5-methoxy-2methyl-3-indolineethanol in ml. of methylene chloride .istreated with365 mg. (2.05 mmol) of pchlorobenzoyl chloride in methylene chloride.The resultingmixtureis stirred at ambient temperature for 16 hoursi''The organic layer is separated, washed with wat e 'rand evaporated togive a white glass.

EXAMPLE 40 Preparation of l-acetyl-3-( 2-bromoethyl)indoline To asolution of 4l0 mg. of l-acetyl-3- indolineethanol in 25 ml. of benzenein an argon atmosphere is added 0.1 17 ml. of phosphorous tribromide andone drop of pyridine. The resultant mixture is heated under reflux for18 hours. The reaction mixture is cooled and the benzene solutiondecanted into 20 ml.

of ice-water and 10 ml. saturated sodium bicarbonate solution. Theorganic solution is separated, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution and dried with magnesiumsulfate solution. The solvent is removed under reduced pressure and theresulting gum is crystallized from an acetone-hexane mixture affordingl-acetyl-3- (2-bromoethyl)indoline, m.p. 82C.

EXAMPLE 4] Preparation of l-acetyl-3-( 2-bromoethyl )5,6-dimethoxyindoline To a partial solution of 254 mg. oflacetyl-5,6-dimethoxy-3-indolineethanol in 25 ml. of benzene in an argonatmosphere is added one drop of pyridine and 0.056 ml. of phosphoroustribromide. The mixture is stirred and heated under reflux for 18 hours.The reaction mixture is cooled and the benzene solution is decanted into20 ml. of ice-water and 5 ml. of saturated sodium bicarbonate solution.The organic solution is separated, washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicextract is dried with magnesium sulfate, evaporated to dryness underreduced pressure and the residual gum crystallized fromacetone-petroleum ether (3060C.) affording l-acetyl-3-( 2-bromoethyl)-5,6- dimethoxyindoline, m.p. l03l05C.

EXAMPLE 42 Preparation of 5-acetyl-6,7-dihydro-5H- l,3-dioxolo[4,5-f]indole-7- ethyl bromide To a partial solution of 1.5 g.of 5-acetyl-6,7-dihydro- 5H-l,3-dioxolo[4,5f]indole-7-ethanol in 150 ml.of benzene purged with argon is added 10 drops of pyridine, and 0.35 ml.of phosphorus tribromide. The mixture is stirred and heated at refluxfor 18 hours. The mixture is cooled and the supernatant liquid is pouredinto ml. of stirred ice-water and 70 ml. of saturated sodium bicarbonatesolution. The organic phase is separated and evaporated under reducedpressure. The residual solid is crystallized from acetone-petroleumether (b.p. 3060C.) affording 5-acetyl-6,7-dihydro-SH-l,3-dioxolo[4.5-f1indole-7-ethyl bromide, m.p. 147l48C.

EXAMPLE 43 Preparation of l-acetyl-5-nitro-3-indolineethylp-toluenesulfonate A solution of 1.0 g. (0.0040 mole) of l-acetyl-5-nitro--3-indolineethanol and 1.5 g. (0.0080 mole) of ptoluenesulfonylchloride in 20 ml. of pyridine is maintained at 0C. for l8 hours. Themixture is poured into ice-water and extracted with ethyl acetate. Theextract is washed with 1N hydrochloric acid, dried over magnesiumsulfate, and concentrated. The residue is crystallized fromether-petroleum ether to yield l-acetyl-S- nitro-3-indoline ethylp-toluenesulfonate, m.p.

ll8120C.

EXAMPLE 44 Preparation of l-acetyl-3-( 2-bromoethyl )--chloroindoline Amixture of 1.19 g. (5 mmol) of lacetyl-5chloro-3- indolineethanol, 0.29ml. of phosphorus tribromide and 3 drops of pyridine in 50 ml. ofbenzene is heated at reflux temperature for 16 hours. The supernatantsolution is decanted from an orange sludge onto cracked ice-water. Theorganic layer is washed with sodium carbonate solution, dried overmagnesium sulfate and evaporated. Trituration of the residue withpetroleum ether (b.p. 3060C.) gives white crystals, m.p. ll5l 17C.Recrystallization from acetone-hexane raises the m.p. to l20121C.

EXAMPLE 45 Preparation of l-acetyl-3-( 2-bromoethyl )-2-methyl-5-methoxyindoline In the manner described in Example 40 from 430 mg. (0.00l 7 mol) 1-acety1-2-methyl-5methoxy- 3- indolineethanol and 440 mg.(0.0017 mole) of phosphorous tribromide there is obtained l-acety1-3-(2-bromoethyl)-2-methyl-5-methoxyindoline as a cream colored solid, m.p.108l 10C.

EXAMPLE 46 Preparation of 3-( 2-bromoethyl )-5-methoxy-2-methyllp-nitrobenzoyl )indoline A mixture of 356 mg. (1.0 mmol) of 5-methoxy-2-methyl- 1 -(p-nitrobenzoyl )-3-indolineethanol and 135 mg. (0.5 mmol) ofphosphorus tribromide in ml. of benzene containing a drop of pyridine isheated at reflux temperature for 16 hours. The organic solution iswashed with a 5% sodium hydroxide solution and then with saline. Thedried solution is evaporated to give an oil that is chromatographed onsilicic acid. After removal of an impurity by elution withhexanemethylene chloride (1:1), the product is eluted with methylenechloride. This material crystallizes from acetonehexane to give yellowcrystals, m.p. 156 /sC.

EXAMPLE 47 Preparation of l-( p-chlorobenzoyl -3 2-chloroethyl)-5-methoxy-2- methylindoline A solution of 500 mg. (2.0 mmol) of5-methoxy-2- methyl-1-(p-chlorobenzoyl)3-indolineethanol and 240 mg.(2.0 mmol) of thionyl chloride in ml. of benzene is heated at refluxtemperature for 2 hours. An additional 240 mg. (2.0 mmol) of thionylchloride is added and the reaction is continued for one hour. Thin layerchromatography now shows the reaction to be complete. The solution isdiluted with benzene, and washed successively with water, sodiumbicarbonate solution and water, dried, and evaporated to give an oil.

EXAMPLE 48 Preparation of 3-( 2-chloroethyl )-5-methoxy-2-methylindolineA solution of 1.45 g. (7.0 mmol) of 5-methoxy-2-methyl-B-indolineethanol in 50 ml. of benzene is treated with 830 mg.(7.0 mmol) of thionyl chloride. The solution is heated at refluxtemperature for one hour and then cooled. Additional benzene is added,and this solution is washed with a 2% sodium hydroxide solution andwater. Removal of the solvent gives the product as a mobile liquid.

EXAMPLE 49 Preparation of l-benzoyl-3-( 2-bromoethyl )-5,6-dimethoxy-2-methylindoline EXAMPLE 50 Preparation of l-acetyl-3-(2-bromoethyl )-5-methoxy-2-methyl-6- nitroindoline To 50 ml. glacialacetic acid is added 2.22 g. (0.00712 mole) ofl-acetyl-3-(2-bromoethyl)-2- methyl-S-methoxyindoline at ice bathtemperature. To this stirred solution is added dropwise with stirring0.448 g. (0.00712 mole) fuming nitric acid. The reaction mixture isstirred at room temperature for one hour, poured onto ice water andextracted with ethyl acetate. The organic extract is washed withsaturated sodium chloride solution, dried over magnesium sulfate,clarified with carbon and evaporated to give an oil. Crystallizationfrom heptane affords l-acetyl-3-(2- bromoethyl)-5-methoxy-2-methyl-6-nitroindoline m.p. l48150C.

EXAMPLE 5 1 Preparation of l-acetyl-3-( 2-bromoethyl)-5-methoxy-2-methyl-6- nitroindoline By the procedure of Example 49treatment of lacetyl-2-methyl-5-methoxy-6-nitro-3-indolineethanol inbenzene with phosphorus tribromide give yellow crystals of l-acetyl-3-(2-bromoethyl )-5-methoxy-2- methyl-6-nitroindoline, m.p. l47 l 50C.

EXAMPLE 52 Preparation of l-acctyl-5-bromo-3-( 2-bromoethyl )indoline Inthe manner described in Example 40 treatment ofl-acetyl-5-bromo-3-indolineethanol with phosphorus tribromide in benzeneis productive of l-acetyl-S- bromo-3-( 2-bromoethyl )indoline.

EXAMPLE 53 Preparation of 5-methoxy-2-methyl- 1 -(p-nitrobenzoyl )-3-indolineethyl methanesulfonate A solution of 1.00 g. of5-methoxy-2-methyl-l-(pnitrobenzoyl)-3-indolineethanol and 1 ml. ofmethanesulfonyl chloride in 20 ml. of pyridine is maintained at C. for18 hours. The mixture is poured into ice-water and extracted with ethylacetate. The extract is washed with 1N hhydrochloric acid, dried overmagnesium sulfate and evaporated to give the methanesulfonate.

EXAMPLE 54 Preparation of N-[ l-acetyl-3-( Z-methanesulfonyloxyethylindolinyl]acetamide A solution of 2.00 g. of N-[ l-acetyl-3-(2-hydroxyethyl)-5-indolinyl]acetamide and 2 ml. of methanesulfonylchloride in ml. of pyridine is maintained at 0C. for 18 hours. Themixture is poured onto a cracked ice-hydrochloric acid mixture, which isthen extracted with methylene chloride. The dried extract is evaporatedto give N-[ 1-acetyl-3-(2- methanesulfonyloxyethyl)-5-indolinyl]acetamide.

EXAMPLE 55 Preparation of 1-acetyl-3-[2-( 4-phenyll -piperazinyl)ethyl]indoline EXAMPLE 56 Preparation ofl-acety1-3-{2-[4-(o-methoxyphenyl)-1-piperazinyl]- ethyl} indoline 1nthe manner described in Example 55, from 2.5 g. of1-acetyl-3-(2-bromoethyl)indoline and 3.5 g. ofl-(o-methoxyphenyl)piperazine there is obtained 1- acetyl-3-{2-[4-(o-methoxyphenyl l -piperazinyl]ethyl}indoline, m.p. 7780C.

EXAMPLE 57 Preparation of l-acetyl-S ,6-dimethoxy-3-l 2-[4-(o-methoxyphenyl l piperazinyl ]ethyl} indoline A solution of 200 mg.of l-acetyl-3-( 2-bromoethyl)- 5,6-dimethoxyindoline and 250 mg. of1-(o-methoxyphenyl)piperazine in 20 ml. of toluene is heated underreflux for 18 hours. The reaction mixture is cooled and filtered, andthe filtrate is evaporated under reduced pressure. The residual gum ispartitioned between ether and water. The organic solution is separated,washed with saturated sodium bicarbonate solution and sodium chloridesolution. The ether solution is dried with magnesium sulfate andevaporated under reduced pressure. The residual gum is crystallized fromether-petroleum ether affording l-acetyl- 5 ,6-dimethoxy-3-{2-[4-(o-methoxyphenyl l 5 piperazinyl]ethyl}-indoline, m.p. l49l50C.

EXAMPLE 58 Preparation of 1-acetyl-5,6-dimethoxy-3-[2-(4-pheny1-lpiperazinyl)ethyl]indoline In the manner described in Example 57treatment of 2.37 g. (7.24 mmol) of l-acetyl-3-(2-bromoethyl)-5,6-dimethoxyindoline with 2.35 g. (14.5 mmol) of l-phenylpiperazine in 150ml. of boiling toluene for 17 hours produces l-acetyl-S ,6-dimethoxy-3-2-( 4- phenyll -piperazinyl )ethyl 1 indoline.

EXAMPLE 59 Preparation of l-acetyl-5,6-dimethoxy-3-2-[4-(p-methoxyphenyl )-3- methyl- 1 -piperazinyl ethyl} indoline In themanner described in Example 57 treatment of 2.30 g. (7.02 mmol) of1-acetyl-3-(2-bromoethyl)-5,6- dimethoxyindoline with 2.90 g. (14.1mmol) of l-(pmethoxyphenyl )-2-methylpiperazine in 150 ml. of boilingtoluene for 15 hours produces l-acetyl-5,6- dimethoxy-3- {2-[4-(p-methoxyphenyl )-3-methyll piperazinyllethyl}indoline.

EXAMPLE 60 Preparation of 1-acetyl-3-{2-[4-(o-methoxyphenyl l-piperaziny1]- ethyl }-5 -nitroindoline A solution of 1.3 g. (0.0033mole) of l-acetyl-S- nitro-3-indolineethanol, p-toluenesulfonate and 1.3g. (0.0068 mole) of l-(o-methoxyphenyl)piperazine in 25 ml. of tolueneis stirred under reflux for 72 hours and then concentrated bydistillation. The residue is diluted with water and extracted with ethylacetate. The organic layer is separated and extracted with 1Nhydrochloric acid and the acidic solution is rendered alkaline with IONaqueous sodium hydroxide and extracted with ethyl acetate. This extractis dried over magnesium sulfate, clarified with activated carbon, andconcentrated to a yellow oil. Pure l-acetyl-3-{2-[4-(omethoxyphenyl l-piperazinyl ethyl -5-nitroindoline m.p. l41143C., is obtained bychromatography using a synthetic magnesia-silica column.

EXAMPLE 61 Preparation of 5-acetyl-6,7-dihydro-7- 2-[ 3-methyl-4-(p-tolyl piperazinyl]ethyl} -5H- 1 ,3-dioxolo[ 4,5-f]indole 1n the mannerdescribed in Example 57, from 850 mg. of 5-acetyl-6,7-dihydro-5l;l-l,3-dioxolo[4,5- f]indole-7-ethyl bromide and 1.23 g. ofZ-methyl-l-(ptolylpiperazine) is obtained 5-acetyl-6,7-dihydro-7-(2-[3-methyl-4-(p-tolyl )piperazinyl ]ethyl} -5l -ll ,3-dioxolo[4,5-f]indole, m.p. l56l57C.

EXAMPLE 62 Preparation of 5-acetyl-6,7-dihydro-7- {2-[ 4-( o-tolyl)piperazinyl ethyll-SH- l ,3-dioxolo[4,5-f]indole In the mannerdescribed in Example 57, from 1.0 g.

27 of 5-acetyl-6,7-dihydro-5H-1,3-dioxolol4,5-f]indole-7- ethyl bromideand 1.23 g. of l-(o-tolylpiperazine) is obtained 5-acetyl-6,7-dihydro-7-2-[ 4( otolyl )piperazinyl ]ethy1}-51-l- 1 ,3-dioxolo[4,5-f]indole, m.p.166168C.

EXAMPLE 63 Preparation of5-methoxy-3-{2-[4-(o-methoxyphenyl)-1-piperaziny1]-ethyl}-2-methyl-1-(p-nitrobenzoyl)indoline 1n the manner described inExample 57 treatment of 5-methoxy2-methy1-1-(p-nitrobenzoy1)-3-indolineethyl methanesulfonate gives the product as a viscous oil.

EXAMPLE 64 Preparation of5-methoxy-2methyl-3-[2-(4-phenyl-1-piperazinyl)-ethyl]-1-(p-nitrobenzoyl)indoline 1n the manner described in Example 57treatment of 3( 2-bromoethyl )-5-methoxy-2-methyl- 1p-nitrobenzoyl)indoline with l-phenylpiperazine gives 5-methoxy-2-methyl-3-[ 2-(4-pheny1-1-piperazinyl)ethyl]-1-(p-nitrobenzoyl)indoline.

EXAMPLE 65 Preparation of5acetyl-6,7-dihydro-7-{2-[4-(m-to1yl)piperazinyl]- ethyl }-5H-1,3-dioxolo[4,5-f]indole In the manner described in Example 57, from 950mg. of 5-acetyl-6,7-dihydro-5ll-1,3-dioxo1o[4,5- f]indle-7-ethyl bromideand 1.2 g. of 1-(mtoly1)piperazine is obtained-acetyl-6,7-dihydro-7-{2-[4-(mtolyl)piperazinyl]ethyl}-5H-1,3-dioxo1o[4,5-f]-indo1e,m.p. 981()3C.

EXAMPLE 66 Preparation of5-acetyl-6,7-dihydro-7-{2-[4-(o-methoxypheny1)-piperazinyl]ethyl}-5H-1,3-dioxo1o[4,5-f]indo1e EXAMPLE 68 Preparation of1 -acety15-methoxy-3- {2-[4-(o-methoxyphenyl 1 piperazinyl lethyl}-2-methylindoline 1n the manner described in Example 57 treatment of 780mg. (2.5 mmol) of 1-acety1-3-(2-bromoethyl)-2- methyl-5-methoxyindolinewith 1.83 g. (9.5 mmol) of 1-(o-meth0xyphenyl)piperazine gives theproduct as white crystals, m.p. 87-89C.

EXAMPLE 69 Preparation of N- 1-acety1-3-[2-(4-o-methoxyphenyl- 1-piperaziny1)- ethyl]-5-indolinyl}acetamide 1n the manner described inExample 57 treatment of N-( 1-acetyl-3-( Z-methanesulfonyloxyethyl )-5-indolinyllacetamide with l-(o-methoxyphenyl)piperazine provides N-1-acetyl-3-[2-(4-o-methoxyphenyl)- l -piperazinyl)ethyl]-5-indo1inylacetamide.

EXAMPLE 70 Preparation of 1-acetyl-5-methoxy-2-methyl-3-[2-( 4-phenyllpiperazinyl )ethyl indoline By the procedure of Example 57 treatment of2.00 g. (10 mmol) of 1-acetyl-3-(2-bromoethyl)-2-methyl-5-methoxyindoline with 3.10 g. (20 mmol) of l-phenylpiperazine furnishesthe product as off-white crystals, m.p. 127129C.

EXAMPLE 71 Preparation of l-acetyl-3- {2-[4-(0-ch1orophenyl 1-piperazinyl 1- ethyl}-5-methoxy-2-methylindoline 1n the mannerdescribed in Example 57 from 400 mg. (0.0013 mole) 1-acetyl-3'(2-bromoethy1)-2-methyl-5- methoxyindoline and 1.12 g. (0.0057 mole) of1-(o-chlorophenyl)piperazine there is obtained 1-acetyl-3-{2-[4-(o-ch1oropheny1)-l-piperazinyl]ethyl}-5-methoxy-2-methylindoline as a cream colored solid, m.p. 125127C.

EXAMPLE 72 Preparation of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4- phenyl-1-piperazinyl)ethyl]indoline A solution of 400 mg. of crude1-(p-chlorobenzoy1)- 3-(2-chlor0ethyl)-5-methoxy-2-methylindoline in 15ml. of dry benzene is treated with 5 ml. of l-phenylpiperazine andheated at reflux temperature for 16 hours. The solution is evaporated,and the residue is distributed between benzene and sodium bicarbonatesolution. The organic layer is washed with saline, dried and evaporated.The residue is crystallized from etherhexane and then recrystallizedfrom acetone-hexane to give crystals.

EXAMPLE 73 Preparation l-acetyl-5-mcthoxy-3 {2-[4-(o-methoxyphenyl)-1-piperazinyl lethyl} -2-methyl6-nitroind0line To 75 m1. toluene is added2.0 g. (0.01 mol) of l-(o-methoxyphenyl)piperazine and 1.34 g. (3.76mmol) of l-acetyl3-( 2-bromoethyl )-5-methoxy-2- methyl-6-nitroindoline.The reaction mixture is stirred under reflux overnight and thenfiltered. The filtrate is concentrated and then extracted with ethylacetate. The organic layer is washed with water, dried over magnesiumsulfate, clarified with activated carbon and concentrated to yield adark amber oil. Purification by chromatography on a syntheticmagnesia-silica adsorbent affords l-acetyl--methoxy-3- {2-[4-(omethoxyphenyl l -piperazinyl ]ethyl }-2-methyl-6- nitroindoline, m.p.146149C.

EXAMPLE 74 Preparation of l-benzoyl-S ,6-dimethoxy-2-methyl-3-[ 2-(4-phenyll piperazinyl )ethyl ]indoline EXAMPLE 75 Preparation ofl-benzoyl-S ,6-dimethoxy-2-methyl-3- {2-[4- (omethoxyphenyl l-piperazinyl ]ethyl} indoline A solution of 1.5 g. (0.0037 mole) ofl-benzoyl-3-(2- bromoethyl)-5,6-dimethoxy-2-methylindoline and 2.2 g.(0.011 mole) of l-(o-methoxyphenyl)piperazine in 50 ml. of benzene isstirred under reflux for 70 hours. The precipitate which forms isseparated by filtration and the filtrate is washed with water, driedover magnesium sulfate, and concentrated to a yellow oil. The oil ispurified by chromatography on a synthetic magnesiasilica adsorbent toyield l-benzoyl-5,6-dimethoxy-2- methyl-3- 2-[4-( o-methoxyphenyl l-piperazinyl]ethyl} indoline as a yellow glass. This substance gives adihydrochloride monohydrate upon treatment with ethereal hydrogenchloride. This salt is obtained from ethanol-ether as white crystals,m.p. l99200C. (decomp.)

EXAMPLE 76 Preparation of l-benzoyl-S ,6-dimethoxy-2-methyl-3- {2-[4-(mchlorophenyl)-l-piperazinyl1ethyl} indoline A solution of 1.5 g.(0.0037 mole) of l-benzoyl-3-(2-bromoethyl)-5,o-dimethoxy-Z-methylindoline and 2.1 g. (0.011 mole) of1-( m-chlorophenyl)piperazine in 50 ml. of benzene is stirred underreflux for 70 hours. The precipitate which forms is separated byfiltration and the filtrate is washed with water, dried over magnesiumsulfate, and concentrated to a yellow oil. Purification of the oil bychromatography using a synthetic magnesia-silica adsorbent affordsl-benzoyl-5,6- dimethoxy-2-methyl-3- {2-[4-(m-chlorophenyl)-1-piperazinyl]ethyl}indoline as a yellow glass.

EXAMPLE 77 Preparation of l-acetyl-5-bromo-3-{2-[4-(o-methoxyphenyl)-1-piperazinyl ]ethyl} indoline In the manner described in Example 55treatment of l-acetyl-5-bromo-3-( 2-bromoethyl )indoline withl-(o-methoxyphenyl)piperazine in refluxing toluene is productive ofl-acetyl-5-bromo-3- {2-[4-( omethoxyphenyl l piperazinyl ]ethyl}indoline.

EXAMPLE 78 Preparation of l-benzoyl-5 ,6-dimethoxy-2-methyl-3- 2-[ 4-(mtrifluoromethylphenyl)- l-piperazinyl]ethyl} indoline In the mannerdescribed in Example 76 treatment of 3.0 g. (0.0074 mole) ofl-benzoyl-3-( 2-bromoethyl)- 5,6-dimethoxy-2-methylindoline with 3.45 g.(0.015 mol) of 1-(m-trifluoromethylphenyl)piperazine gives1-benzoyl-S,6-dimethoxy-2-methyl-3- {2-[ 4-( mtrifluoromethylphenyl 1-piperazinyl]ethyl} indoline. An ethereal solution of the last substanceis treated with hydrogen chloride, and the solid which results isrecrystallized from acetonitrile to give the monohydrochloride as whitecrystals, m.p. 232233C. dec.

EXAMPLE 79 Preparation of 3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline Asolution of 4.4 g. ofl-acetyl-3-[2-(4-phenyl-lpiperazinyl)ethyl]indoline and 80 m1. of 6Nhydrochloric acid is heated under reflux for 30 minutes. The solution isconcentrated under reduced pressure to 10 ml., diluted with water andrendered alkaline with sodium hydroxide solution. The alkaline solutionis extracted with ether. The ether extract is washed with saturatedsodium chloride solution, dried with magnesium sulfate and evaporatedunder reduced pressure affording 3.4 g. of3-[2-(4-phenyl-1-piperazinyl)ethyl]indoline. The dimaleate salt has m.p.13914lC.

EXAMPLE 80 Preparation of 3-{2-[4-( o-methoxyphenyl l -piperazinyl]ethyl} indoline According to the manner described in Example 79, 1.20g. of l-acetyl-3-{2-[4-(o-methoxyphenyl)-1- piperazinyl]ethyl}indolineand 25 ml. of 6N hydrochloric acid gives 3- {2-[4-( o-methoxyphenyl)- lpiperazinyl]ethyl} indoline trihydrochloride, m.p. 248250C.

EXAMPLE 81 Preparation of 6,7-dihydr0-7- {2-[ 4-( o-methoxyphenyl)piperazinyl ethyl} -5H-l ,3-dioxolo[ 4,5-f]indole difumarate A solutionof 500 mg. of 5-acetyl-6,7-dihydro-7-{2- [4-(o-methoxyphenyl)piperazinyl]ethyl}-5H- l ,3- dioxolo[4,5-f]indole and 10 ml. of 6Nhydrochloric acid is heated at reflux for 15 minutes. The solution istreated with activated charcoal, filtered and evaporated under reducedpressure. The residual gum is evaporated several times with ethanol. Theresulting glass is dissolved in ethanol, treated with activated charcoaland the solvent removed under reduced pressure. The residual glass isdissolved in water. The aqueous solution is rendered alkaline with IONsodium hydroxide, and extracted with ethyl acetate. The ethyl acetatesolution is evaporated under reduced pressure affording 6,7-dihydro-7-{2-[4-(0- methoxyphenyl)piperazinyl1ethyl} -5 H- l ,3-dioxolo[4,5-f]indole, the difumarate of which has m.p. l93 195C.

EXAMPLE 82 Preparation of 6,7-dihydro-7- 2-[3-methyl-4-( p-tolyl)piperazinyl ethyl }-H- 1 ,3-dioxolo[ 4,5-f]indole EXAMPLE 83Preparation of 6,7-dihydro-7- {2-[4-(m-tolyl )piperazinyl ]ethyl}-5l-ll,3dioxolo[4,5-f]indole In the manner described in Example 82, from500 mg. of 5-acetyl-6,7-dihydro-7-{2-[4-(mtolyl )piperazinyl1ethyl} -5H-1 ,3-dioxolo[4,5-f]indole and ml. of 6N hydrochloric acid is obtained6,7- dihydro-7- {2-[ 4-(m-tolyl )piperazinyl ]ethyl} 5H- 1 ,3- dioxolo[4,5-f1indoline trihydrochloride.

EXAMPLE 84 Preparation of 5-bromo-3-{2-[4-(o-methoxyphenyl)-l-piperazinyl1- ethyl }indoline In the manner described in Example 82 asolution of l-acetyl-5-bromo-3-{2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl}-indoline in 6N hydrochloric acid is heated at refluxtemperature for minutes. Removal of the solvent furnishes thehydrochloride salt of '5- bromo-3-i2-[4-( o-methoxyphenyl l -piperazinylethyl} indoline.

EXAMPLE 85 Preparation of 6,7-dihydro-7-{2-[4-( o-tolyl)piperazinyl]ethyl} -5H- 1 ,3-dioxolo[ 4,5-f1indole In the mannerdescribed in Example 82, from 500 mg. of5-acetyl-6,7-dihydro-7-{2-[4-(0-tolyl)piperazinyl]ethyl}-5H-1,3-dioxolo[4,5-f]indoline and 10 ml. of 6Nhydrochloric acid is obtained 6,7- dihydro-7-{2-[4-(o-tolyl )piperazinyl]ethyl}-5 H- l ,3- dioxolo[4,5-f]indole trihydrochloride.

EXAMPLE 86 Preparation of 5-methoxy-2-methyl- 3-[2-(4-phenyl-1-piperazinyl)- ethyl ]indoline In the manner described inExample 79, from 1.86 g. (4.7 mmol) ofl-acetyl-5-methoxy-2-methyl-3-[2-(4- phenyl-l-piperazinyl)ethyl]indolineand 60 ml. of 6N hydrochloric acid is obtained 5-methoxy-2-methyl-3-[2-(4-phenyl-l-piperaziny])ethyl]indoline as white crystals, m.p. 6467C.

EXAMPLE 87 Preparation of 5-methoxy-3- 2-[4-( o-methoxyphenyl l-piperazinyl]- ethyl -2-methylindoline In the manner described inExample 79, from 2.52 g. (5.9 mmol) of l-acetyl-5-methoxy-3-{2-[4-(0-methoxyphenyl l-piperazinyl ethyl -2- methylindoline and ml. of 6Nhydrochloric acid is obtained 5-methoxy3-{ 2-[4-( o-methoxyphenyl 1piperazinyl]ethyl}-2-methylindoline as white crystals, m.p. 9293C.

EXAMPLE 88 Preparation of 3-{ 2 [4-( o-chlorophenyl l-piperazinyl]ethyl} -5- methoxy-2-methylindoline 1n the manner describedin Example 79, from 1.25 g. (2.9 mmol) of l-acetyl-3-{2-[4-(0-chlorophenyl)- lpiperazinyl]-ethyl} -5-rnethoxy-2-methylindoline and50 ml. of 6N hydrochloric acid is obtained 3-{ 2-[4-(0- chlorophenyl l-piperazinyl ]ethyl -5-methoxy-2- methylindole as off-white crystals,m.p. l09l 10C.

EXAMPLE 89 Preparation of 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-1-piperazinyl )ethyl indoline A solution of 0.32 g. (0.00066 mole) ofl-benzoyl- 5 ,6-dimethoxy-2-methyl-3-[ 2-( 4-phenyllpiperazinyl)ethyl]indoline in 10 ml. of 6N hydrochloric acid is stirredunder reflux for 30 minutes and then poured into 50 ml. of ice-coldaqueous sodium bicarbonate solution. The mixture is rendered alkalinewith lON sodium hydroxide solution and extracted with methylenechloride. The extract is dried over magnesium sulfate and concentratedto a yellow oil. Crystallization from ether affords5,6-dimethoxy-2-methyl-3- 2-(4-phenyl-1-piperazinyl)ethyl]indoline, m.p.1 12--] 13C.

EXAMPLE 90 Preparation of 5-methoxy-2methyl-3-[ 2-( 4-phenyll-piperazinyl ethyl ]indoline 1n the manner described in Example 79 asolution of 5-methoxy-2-methyl-3-[ 2-( 4-phenyllpiperazinyl)ethyl]-l-(p-nitrobenzoyl)indoline in 6N hydrochloric acid isheated at reflux temperature for 15 minutes. Removal of the solventfurnishes S-methoxy-2-methyl-3-[2-(4-phenyl-l-piperazinyl)ethyllindoline as white crystals,m.p. 6467C.

EXAMPLE 91 Preparation of 5-methoxy-3-{2-[4-(omethoxyphenyl lpiperazinyl]ethyl} -2-methylindoline In the manner described in Example79 a solution of 5-methoxy-3-{ 2-[ 4-( o-methoxyphenyl l piperazinyl]ethyli-Z-methyll p-nitrobenzoyl )indoline in 6N hydrochloric acid isheated at reflux temperature for 15 minutes. Removal of the solventfurnishes 5-methoxy-3-{ 2-[ 4-(o-methoxyphenyl l piperazinyllethyl}-2-methylindoline as white crystals, m.p. 9093C.

EXAMPLE 92 Preparation of 3- {2-{ 4-( o-methoxyphenyl l -piperazinyljethyl nitroindoline dihydrochloride A mixture of 1.0 g. (0.0024 mole)of l-acetyl-3-{2- [4-( o-methoxyphenyl l -piperazinyl ]ethyl l-5-nitroindoline and 20 ml. of 6N hydrochloric acid is stirred under refluxfor minutes. Concentration affords a yellow oil which is crystallizedfrom methanolethanol to yield3-{2-[4-(o-methoxyphenyl)-lpiperazinyl1ethyl} -5-nitroindolinedihydrochloride, m.p. 243246C. dec.

EXAMPLE 93 Preparation of 1-acetyl-3- {2[ 4-(omethoxyphenyl 1piperazinyl ethyl }-5-aminoindoline A mixture of 1.0 g. (0.0024 mole) ofl-acetyl-3-{2 [4-( omethoxyphenyl l -piperazinyl]ethyl} 5-nitroindoline, 0.20 g. of 83% platinum oxide, ml. of 6N hydrochloricacid, and 50 ml. of ethanol is shaken under hydrogen pressure for onehour. The catalyst is separated by filtration and the solvent removed byconcentration. The residue is partitioned between water and methylenechloride and the aqueous layer is separated and rendered alkaline usingaqueous sodium hydroxide solution, and extracted with methylenechloride. The extract is dried over anhydrous magnesium sulfate,clarified using activated carbon, and concentrated to yieldl-acetyl-3-{2-[4-(o-methoxyphenyl)-lpiperazinyl ]-ethyl}-5-aminoindolineas a yellow oil.

EXAMPLE 94 Preparation of 3- {2-[ 4-( o-methoxyphenyl l -piperazinyl]ethyl} -5- aminoindoline hydrochloride A solution of 0.90 g. (0.0023mole) of l-acetyl-3-{2- [4-( o-methoxyphenyl l -piperazinyl]ethyl}-5-aminoindolinc in 20 ml. of 6N hydrochloric acid is hcated on a steambath for 30 minutes. The solution is clarified with activated carbon andconcentrated. Dilution of the residue with ether followed by filtrationaffords 3-{2-[4-( o-methoxyphenyl l piperazinyl lethyl} -5aminoindolinehydrochloride, m.p. l85l95C. dec.

EXAMPLE 95 Preparation of 5-amino-3- {2[ 4-( o-methoxyphenyl l-piperazinyl ethyl}indoline hydrochloride In the manner described inExample 82 a solution of N{ l-acctyl-3-[2-( 4-o-methoxyphenyll-piperazinyl)ethylj-5-indolinyl} acetamide in 6N hydrochloric acid isheated at reflux temperature for 15 minutes. Removal of the solventfurnishes a gray powder, m.p. l83l90C. dec.

EXAMPLE 96 Preparation of l-acetyl3- (2-[ 4-( o-methoxyphenyl l-piperazinyl 1- ethyl }-5-dimethylaminoindolinc A mixture of 0.39 g.(0.0010 mole) of l-acetyl-3-{2- [4-( o-methoxyphenyl l -piperazinyllethyl }5- aminoindoline, 2.2 ml. formic acid, and 0.23 ml. of

37% aqueous formaldehyde is stirred under reflux for 5 hours. Thesolution is diluted with 1N hydrochloric acid and extracted withetherethyl acetate. The aqueous layer is separated, rendered alkalineusing aqueous sodium hydroxide solution, and extracted with ethylacetate. The extract is dried over anhydrous magnesium sulfate andconcentrated to yield l-acetyl-3-{2-[4-(omethoxyphenyl l-piperazinyl]ethyl} -5- climethylaminoindoline as a yellow gum.

EXAMPLE 97 Preparation of 3- {2-[4-(o-methoxyphenyl l -piperazinyl]ethyl}-5- dimethylaminoindoline In the manner described in Example 82,l-acetyl-3- 2- 4-( o-methoxyphenyl l -piperazinyl lethyl -5-dimethylaminoindoline is hydrolyzed to 3- {2-[4-(o methoxyphenyl l-piperazinyl]-ethyl} -5- dimethylaminoindoline.

EXAMPLE 98 Preparation of 5 ,6-dimethoxy-3- {2[4-( o-methoxyphenyl 1piperazinyllethyl} indoline In the manner described in Example 82 asolution of 2.57 g. (5.85 mol) of l-acetyl-5,6-dimethoxy-3-{2-[4-(o-methoxyphenyl)-l-piperazinyl]ethyllindoline in ml. of 6N hydrochloricacid is heated at reflux temperature for 15 minutes. Removal of thesolvent furnishes the hydrochloride salt of 5,6-dimethoxy3-{2-[4-(0-methoxyphenyl)-l-piperazinyl]ethyl} indoline as a glass.

EXAMPLE 99 Preparation of 5,6-dimethoxy-2-methyl-3-{ 2-[ 4-(mtrifluoromethylphenyl l -piperazinyl ]ethyl} indoline In the mannerdescribed in Example 82 a solution of l-benzoyl-5,6dimethoxy-2-methyl-3-{ 2-[ 4-( mtrifluoromethylphenyl)- l -piperazinyllethyl} indoline in 6N hydrochloric acid is heated at reflux temperaturefor 15 minutesl. Removal of the solvent furnishes a hydrochloride saltof 5,6-dimethoxy2-methyl-3-{2-[4 (m-trifluoromethylphenyl l -piperazinylethyl} indoline.

EXAMPLE Preparation of 5-chloro-3- {2-[4( m-tolyl )-3-methyll-piperazinyl]- ethyl}indoline In the manner described in Example 82 asolution of l -acetyl-5-chloro-3- {2-[4-( m-tolyl )3-methyllpiperazinyHethyl}-indoline in 6N hydrochloric acid is heated at refluxtemperature for 15 minutes. Removal of the solvent furnishes thehydrochloride salt of the product.

Removal of the solvent furnishes the hydrochloride salt of5,6-dimethoxy-3-{2-[4-(p-methoxyphenyl)-3- methyl- 1 -piperazinyl]ethyl}indoline.

EXAMPLE 102 Preparation of ,6-dimethoxy-3-[ 2-( 4-phenyll -piperazinyl)ethyl indoline ]n the manner described in Example 82 a solution ofl-acetyl-5 ,6-dimethoxy-3-[2-( 4-phenyl l piperazinyl)ethyl]indoline in6N hydrochloric acid is heated at reflux temperature for minutes.Removal of the solvent furnishes5,6-dimethoxy-3-[2-(4-phenyll-piperazinyl )ethyl indolinetrihydrochloride.

EXAMPLE 103 Preparation of 5-methoxy-2methyl-3-[ 2-( 4-phenyll-piperazinyl)- ethyl ]indoline [n the manner described in Example 79 asolution of l-( p-chlorobenzoyl )-5-methoxy-2-methyl-3-[ 2-( 4- 3.l-Acetyl-3-( 2-bromoethyl )-5 ,6-dimethoxyindoliner 4.l-Acetyl-5-nitro-3-indolineethyl-p-toluenesulfon- 2R6.

5. 1-Benzoyl-5,6-dimethoXy-2-methyl-3- indolineethanol.

6. 5-Acetyl-6,7-dihydro-5H- l ,3-dioxolo 4,5-f1- indole-7-ethanol.

7. l-Acetyl-5,6-dimethoxy-3-indolineethanol. 8.l-Acetyl-5-methoxy-2-methyl-L t-indolineethanol. 9.l-Acetyl-3-(2-bromoethyl)-5-chloroindoline

1. 1-BENZOYL-3-(2-BROMOETHYL)-5,6-DIMETHOXY-2-METHYLINDOLINE.
 2. 5-Acetyl-6,7-dihydro-5H-1,3-dioxolo(4,5-f)-indole-7-ethyl bromide.
 3. 1-Acetyl-3-(2-bromoethyl)-5,6-dimethoxyindoline.
 4. 1-Acetyl-5-nitro-3-indolineethyl-p-toluenesulfonate.
 5. 1-Benzoyl-5,6-dimethoxy-2-methyl-3-indolineethanol.
 6. 5-Acetyl-6,7-dihydro-5H-1,3-dioxolo(4,5-f)-indole-7-ethanol.
 7. 1-Acetyl-5,6-dimethoxy-3-indolineethanol.
 8. 1-Acetyl-5-methoxy-2-methyl-3-indolineethanol.
 9. 1-Acetyl-3-(2-bromoethyl)-5-chloroindoline. 